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(Chest. 2003;123:356S-362S.)
© 2003 American College of Chest Physicians

The Functional Consequences of Structural Changes in the Airways*

Implications for Airway Hyperresponsiveness in Asthma

Lu Wang, MD, PhD; Brent E. McParland, PhD and Peter D. Paré, MD

* From the McDonald Research Laboratories (Drs. McParland and Paré), University of British Columbia McDonald Research Laboratories, iCAPTURE Center, St. Paul’s Hospital, Vancouver, BC, Canada; and the Section of Respiratory Diseases (Dr. Wang), Asthma/COPD Research Centre, Department of Pediatrics, John Buhler Research Centre, University of Manitoba, Winnipeg, MB, Canada.

Correspondence to: Peter D. Paré, MD, McDonald Research Laboratories/the iCAPTURE Center, St. Paul’s Hospital, Burrard Building, 1081 Burrard St, Vancouver, BC, V6Z 1Y6 Canada; e-mail: ppare{at}mrl.ubc.ca


   Introduction
TOP
 Introduction
Structural Alterations
 Functional Consequences
 Summary
 References
 
Over the last decade, there has been increasing recognition that structural change (ie, remodeling) in the airways of asthmatic subjects is a characteristic feature of the disease and may have important functional implications. Remodeling can be defined as changes in the composition, content, and organization of the cellular and molecular constituents of the airway wall.

The recent interest in airway remodeling in asthma patients is highlighted by doing a PubMed search by decade since 1980 using the following key words (Table 1 ): asthma and airway smooth muscle; asthma and inflammation; and asthma and airway remodeling.


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  		Table 1.. Number of Reports Available in PubMed Database

 
The most important functional abnormality of asthmatic airways is their ability to narrow excessively in response to the inhalation of substances that cause airway smooth muscle (ASM) contraction. We will summarize the quantitative structural changes that have been described in the airways of asthmatic subjects and will speculate as to the potential functional consequences of these structural changes, specifically with reference to airway hyperresponsiveness. The geometric effects of airway wall thickening have been described in previous publications. In this brief review, we will emphasize some newer concepts, such as the idea that airway wall remodeling could alter the degree of radial constraint of in situ ASM, and the idea that remodeling could decrease airway distensibility and allow the ASM to adapt to shorter lengths.


   Structural Alterations
TOP
 Introduction
 Structural Alterations
Functional Consequences
 Summary
 References
 
The structural changes that occur in the airways of asthmatic subjects are thought to come about by repeated injury and repair.1 2 3 4 It is likely that repeated and/or persistent inflammation and epithelial damage to the airways of asthmatic subjects5 leads to a dysregulation of the repair process and to the deposition of excessive extracellular matrix, angiogenesis, and cellular hypertrophy/hyperplasia. The structural changes are characterized by an increase in the thickness of all airway wall layers6 7 with phenotypic changes8 9 in the constituents of the layers. In the epithelial layer, there is mucus-secreting goblet cell hyperplasia with goblet cells extending more peripherally into the tracheal-bronchial tree.10 11 In addition, there is evidence that the epithelial layer is thickened1 even though epithelial damage and sloughing also are observed12 in severe cases. The most characteristic and repeatedly described structural change in the airways of asthmatic subjects is the increase in the thickness of the reticular layer of dense fibrous connective tissue immediately below the basement membrane.13 Roche and coworkers14 have shown that this thickened subepithelial "basement membrane" consists of a dense layer that is rich in fibrillar collagens and is under a normal subepithelial basal lamina. This distinct collagenous matrix layer is typically doubled in thickness from 5 to 8 µm (normal range) to 10 to 15 µm (asthma), and contains types I, III, and V collagen and fibronectin14 but not basal lamina components (ie, type IV collagen and laminin). This collagenous matrix may be synthesized by its associated myofibroblasts since myofibroblast number correlates with the magnitude of subepithelial thickening.15 Similar structural changes have been observed in patients with mild asthma and in patients with occupational asthma associated with exposure to a variety of chemicals.16 Holgate and colleagues17 have proposed that "the airway epithelium and the underlying myofibroblasts act together as a trophic unit and that impaired epidermal growth factor receptor-mediated repair cooperates with the T(H[helper])2 environment to cause myofibroblast activation, excessive matrix deposition, and production of mediators that propagate and amplify the remodeling responses throughout the airway wall."

Below the basal lamina, and in the adventitial space between the muscle layer and the surrounding parenchyma, there is a rich plexus of bronchial microvessels. In addition to providing nutrition to the airways, these vessels are the source of inflammatory cells and of plasma-derived mediators and cytokines.9 18 Moreover, the vessels can contribute to airway narrowing by dilating and forming edema.19 There is convincing evidence that there is an increase in the number and size of the vessels in these vascular plexuses in patients with asthma.2 4 20 21

ASM volume is increased in asthma patients, especially in those who have fatal asthma. Ebina and colleagues3 22 have reported two patterns of ASM hypertrophy and hyperplasia. In their type 1 asthmatic patients, ASM mass was increased only in the central bronchi, where hyperplasia predominated. In type 2 asthmatic patients, there was increased muscle throughout the tracheobronchial tree, and the increased muscle was characterized by hyperplasia as well as hypertrophy, especially in peripheral airways. Thomson et al23 suggested that the increase in ASM area that has been reported in asthma patients could have been overestimated. These investigators measured the ASM area in the large central airways of five asthmatic subjects and showed no significant difference compared to a matched control group despite the observation that the airway preparations generated more isometric force.24 However, Thomson et al23 studied only large central cartilaginous airways, and most of the reports of an increase in ASM area have examined peripheral airways.

Finally, the layer between the ASM and the surrounding parenchyma is increased in thickness in asthma patients. This adventitial layer is made up of loose connective tissue and bronchial microvessels, both of which are increased in asthma patients and are accompanied by an inflammatory cell accumulation.

Much of the work that has been done to quantify the structural changes of the airways in asthma patients has relied on the concept, originally supported by the work of James et al,25 that the basement membrane perimeter length of airways is constant in human airways despite different degrees of ASM contraction and different degrees of lung inflation at the time of fixation. This concept has been challenged by McParland et al.26 These investigators showed that when human large airways were inflated to a transmural pressure of 21 cm H2O, the basement membrane length increased by approximately 50% over its calculated length at 0 transmural pressure. Since the airways of asthmatic subjects, especially those with fatal cases of the disease, are constricted at the time of pathologic examination (and often are not inflated with fixative) and the comparison lungs of nonasthmatic patients are not constricted and are often inflated, a systematic overestimate of all airway wall compartment areas may have occurred in many of these studies.


   Functional Consequences
TOP
 Introduction
 Structural Alterations
 Functional Consequences
Summary
 References
 
A discussion of how structural changes in the airway wall can influence airway function is facilitated by consideration of the standardized nomenclature used to describe airway wall compartments, as given by Bai et al27 and Kuwano et al2 (Fig 1 ). These authors defined three functionally distinct layers to the wall, and the thickening of each can have separate effects, as shown in Table 2 . The thickening of the inner airway wall layer (ie, epithelium, lamina reticularis, and loose connective tissue between the lamina reticularis and the ASM layer) can amplify the effect of ASM shortening,1 25 the thickening of the outer (or adventitial) layer could decrease the static and dynamic loads on the ASM, and an increase in the ASM layer thickness can increase the strength of the muscle.28 In addition, the remodeling of the connective tissue in the smooth muscle compartment could increase or decrease the amount of radial constraint provided to the ASM. Finally, thickening and fibrous connective tissue deposition in all layers could decrease airway distensibility and allow ASM adaptation to shorter lengths.



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  		Figure 1.. Schematic diagram of the airway with compartments. Po = outer adventitial perimeter; Pe = smooth muscle perimeter; Pbm = basement membrane perimeter; Ao, Ae, and Abm = areas subtended by Po, Pe, and Pbm, respectively. Adapted from Kuwano et al.2

 

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  		Table 2.. Structural and Functional Changes in Asthmatic Airways

 
Although remodeling is believed to enhance airway narrowing, it also could protect against excessive narrowing. Lambert et al28 have proposed that when the airways narrow, the folding of the mucosal membrane internal to the ASM layer provides a load to the muscle. Thickening and stiffening of this layer could increase the load and attenuate the ability of ASM to narrow the airway lumen. Wiggs et al29 modeled this layer as two concentric sublayers of tissue having homogeneous but different Young moduli. They found that the force necessary to generate the mucosal folds would increase with the thickness and stiffness of the layers. However, the actual load provided by the folding is very difficult to calculate because it requires knowledge of the micromechanical properties of the constituents of the internal airway wall, both in tension and in compression, since during ASM contraction both tension and compression are imposed on components of the internal airway wall. Thus, although thickening of the inner wall will undoubtedly enhance the effect of ASM shortening, the thickening could itself attenuate the ability of the muscle to shorten.

The functional consequence of the thickening of the adventitial layer between the ASM and the surrounding parenchyma is similarly complicated. On the one hand, the thickening of this layer could increase the ability of the ASM to narrow the airway. The lung parenchymal recoil provides an important load for ASM, and thickening of this layer functionally uncouples the ASM from the surrounding recoil. Thus, the muscle is able to shorten more before the surrounding parenchyma is distorted to the same extent. However, this scenario assumes that the material that makes up the thickened adventitial space is relatively malleable in nature. If fibrous connective tissue is laid down in this layer, the airways could become stiffer. On the one hand, this could negate to some extent the geometric and interdependence effects, but on the other hand it could interfere with the ability of tidal breathing and/or deep inspiration to stretch the ASM.

Irrespective of whether the increase in ASM volume in asthma patients represents hypertrophy or hyperplasia, an increase in ASM amount could be a powerful force in determining the degree of ASM shortening. Lambert et al7 modeled the tracheal-bronchial tree to examine the influence of increases in wall thickening in all layers as well as the alteration in the surrounding parenchymal recoil. In his modeling, he found that the single most important factor leading to an increased potential for airway narrowing following bronchoconstricting stimuli was an increase in ASM amount. However, this modeling was based on the assumption that an increase in the amount of muscle is accompanied by a parallel increase in the ability of that muscle to generate force. It is unclear whether this is in fact the case. Unfortunately, there have been few studies in which the functional properties of ASM from asthmatic subjects have been measured and corrected for the amount of ASM in the preparation. Schellenberg et al24 have reported increased maximal isotonic shortening and increased isometric force generation in a single asthmatic bronchial smooth muscle specimen, despite a normal amount of smooth muscle. Both de Jongste et al,30 and Bai31 have reported increased maximal force generation in the central airways of asthmatic subjects, however, they did not correct the force for the amount of smooth muscle in the airways. Although one might expect that an increase in ASM mass would be accompanied by an increase in force generation, this is not necessarily the case. Vascular smooth muscle proliferation induced in rabbits by hyperoxia produces an increase in smooth muscle mass, but a decrease in the maximal stress-generating ability of the vascular smooth muscle.32 When ASM is subjected to chronic inflammatory stimuli, it is possible that there is differentiation of the ASM to a more synthetic phenotype such that the ability of the muscle to generate force and to shorten does not increase in parallel with mass. This phenomenon is best exemplified by the striking phenotypic changes that occur in ASM when it is cultured and allowed to proliferate in vitro. When ASM is stimulated to proliferate, the muscle differentiates from a contractile to a more motile phenotype, concomitant with decreased {alpha}-smooth muscle actin content and increased ß-actin and non-muscle myosin content with increasing time in culture.33 Similarly, the contractile capacity of the cells decreases unless these cells are serum-starved, which results in the selection or formation of a subset of highly contractile cells.

Some of the increase in the ASM layer thickness in asthma patients may be due to the deposition of matrix elements between muscle cells and bundles.23 It is unclear how this remodeling of the connective tissue framework of the muscle layer will affect function. The connective tissue could constrain the muscle and attenuate its ability to shorten. The concept of radial constraint was proposed by Meiss.34 Meiss showed that when the ability of the canine tracheal muscle to expand radially during contraction was constrained by silastic bands, it shortened less. Indeed, he found that normal canine tracheal smooth muscle might have intrinsic radial constraint since mild digestion with collagenase caused a slight but significant increase in smooth muscle shortening. The potential for radial constraint to modulate ASM shortening is greater in human airways since the muscle layer contains much more connective tissue than canine airways.23 This phenomenon may then be an explanation for the striking increases in ASM contractility that was reported by Bramley et al35 following the incubation of human ASM preparations with collagenase. The average ASM shortening in such preparations is substantially less than that observed in the canine or porcine tracheal smooth muscle preparations (ie, approximately 15% vs 70%, respectively). Following incubation with collagenase, there was an approximate 50% increase in maximal shortening. Ultrastructural studies have shown that individual ASM cells are surrounded by a basal lamina containing type I and IV collagen and additionally that collagen bundles are woven throughout the ASM. Inflammatory remodeling could increase or decrease radial constraint to modulate ASM shortening. During acute episodes of inflammation, the release of proteolytic enzymes could decrease the radial constraint by fragmenting connective tissue elements. However, during the repair phase, the synthesis and deposition of matrix components could have the opposite effect.

The final mechanism by which airway remodeling could enhance airway narrowing is by decreasing airway distensibility, leading to ASM adaptation to short lengths. The concept that ASM can rapidly adapt its length-tension relationship was first demonstrated by Pratusevich et al.36 Adaptation or plasticity refers to the capacity of smooth muscle to alter the position of its length-tension curve. In skeletal and cardiac muscle, in which well-defined sarcomeres are the functional unit and overlap between actin and myosin within sarcomeres is critical for force and shortening, adaptation is a very slow process. Adaptation can occur when a skeletal muscle is kept at long or short lengths for prolonged periods of time, as occurs in animal models of emphysema or when a limb is held in a nonphysiologic position during casting. However, the ability of ASM to alter its length-tension curve is a rapid phenomenon occurring over a period of half an hour. Although the mechanism by which this occurs is unknown, it is likely that the shift in the length-tension curve stems from the variation in the number of contractile units in series, similar to the in-series sarcomere number change observed in skeletal muscle.37

We38 39 also have examined another phenomenon, which is the ability of ASM to adapt to a shorter or longer length when held at that length for a period of between 6 and 24 h. Rabbit tracheal smooth muscle was maintained at lengths shorter than or longer than its resting length at 4°C for periods between 6 and 24 h, and then length-tension relationships were constructed. Figure 2 illustrates the results of one such experiment 24 h after the length changes were imposed. It is apparent that both the passive and the active length-tension relationship are shifted to shorter and longer lengths, respectively, in tissues that are held at short and long lengths. Similar results were apparent at 12 h but not at 6 h following the length changes.39 This bidirectional shift in the length-tension curve of unstimulated ASM implies that the subcellular components governing the length-tension relationship can be restructured according to the length of the passively shortened or lengthened muscle cells. The shift in passive length-tension curve was as drastic as the active length-tension curve, which implies that it is likely that the restructuring of the cytoskeleton and/or the extracellular scaffolding filaments also is involved in the adaptation process. Furthermore, the passive shift indicates that airway tone is critically influenced by the length at which the muscle is adapted. The potential for this phenomenon to contribute to excessive airway narrowing is obvious. In asthma patients, there are a number of mechanisms by which the ASM can be shortened for prolonged periods of time. First, there could be active shortening during attacks of asthma in which mediator release and neural stimuli maintain the ASM at short lengths for prolonged periods. In addition, there is the potential for passive shortening of the smooth muscle along its passive length-tension relationship. This could occur because of an accumulation of edema or congestion within the adventitial space of the airway that is caused by vascular leakage and dilatation of the bronchial microvasculature. With muscle adaptation, the same maximum force produced by muscle at normal length can be generated by shortened muscle. This could create a catastrophic situation in which chronically narrowed airways can constrict further. The shifting of the passive length-tension curve further exacerbates the situation. Even without ASM contraction, the leftward shift of the passive length-tension curve in the shortened muscle makes distension of the airways more difficult.



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  		Figure 2.. Adaptation of ASM length-tension curves of the rabbit trachealis muscle. Left, A: comparison between a passively shortened muscle preparation (•) and a reference preparation ({circ}) from one trachea. Right, B: comparison between a passively lengthened muscle preparation (•) and a reference preparation ({circ}) from another trachea. Top, A and B: active force. Circles represent the measured force at various lengths, and lines represent the Weibull 4-parameter function fitted to the data. Bottom, A and B: passive force at various lengths. Adapted from Wang et al.38

 
The mechanism by which ASM adapts itself and alters its length-tension curve remains uncertain. Gunst et al40 have suggested that remodeling of the cytoskeleton is required, and clearly this must be the case. In addition, Wang and colleagues38 41 42 have proposed that there is remodeling of the contractile apparatus with the addition or subtraction of contractile units in series to explain the maintenance of force at long and short lengths. Their premise that contractile element remodeling is necessary is based on their finding that, although force generation remains constant after plastic rearrangement, the velocity of smooth muscle contraction increases linearly with smooth muscle length. This could be accomplished only by adding contractile units in series rather than by lengthening existing contractile units. In fact, Kuo and colleagues43 have obtained ultrastructural evidence to support their observations. When a length perturbation, comparable to a deep inspiration in vivo, was applied to a tracheal smooth muscle preparation, the density of myosin thick filaments decreased drastically and then recovered during the adaptation process.43 When the muscle length was doubled, the density of thick filaments per cell increased by 68%, which is almost identical to the increase in muscle velocity of shortening and power, and to the adenosine triphosphate synthase rate caused by muscle lengthening. These data suggest that there is contractile element remodeling during the adaptation process. Indeed, there is a pool of soluble myosin in ASM, and presumably this pool forms the basis of the evanescence of filamentous myosin during length adaptation.

Whatever the mechanism, the adaptation of the ASM length-tension curve to altered lengths has potential functional importance. ASM adaptability or plasticity may, in part, explain the bronchodilating and bronchoprotective effect of deep inspiration. During a deep inspiration, the contractile apparatus could disassemble due to its intrinsic plasticity in order to adapt to the new geometry of the ASM cell. As a functional consequence, there could be a temporary loss of the ability of ASM to generate maximal force,41 reversing airway narrowing. Airway remodeling, particularly subepithelial and adventitial fibrosis could impair plasticity by decreasing the transmission of distending forces to the ASM and could allow it to adapt to a shorter length.


   Summary
TOP
 Introduction
 Structural Alterations
 Functional Consequences
 Summary
References
 
In this manuscript, we have briefly reviewed the mechanisms by which structural changes in the airway wall can interact with ASM to alter or modulate the ability of the ASM to narrow the airway. Airway wall thickening internal to the ASM layer can amplify the effect of ASM shortening. Airway wall thickening outside the ASM layer could decrease the static and/or dynamic loads on the ASM, allowing it to shorten more. On the other hand, these purely geometric detrimental effects may be decreased if the constituents of the remodeled compartments have altered mechanical properties stiffening the airway wall and providing an increased load for the muscle. An increase in ASM itself, if accompanied by a maintained contractile phenotype, would increase the strength of the ASM, allowing it to overcome dynamic and static loads. Connective tissue elements, by providing a radial constraint to ASM, could attenuate its ability to shorten and narrow the lumen. Alternatively, proteolytic digestion of the connective tissue elements within the ASM layer could transiently or permanently decrease the radial constraint provided by connective tissue elements, allowing excessive ASM shortening. Finally, the ability of the ASM to adapt to altered length has potential consequences that could provide a positive feedback loop, enhancing the ability of the smooth muscle to narrow the airways. ASM that is shortened either actively or passively during acute attacks of asthma could adapt to a shortened length and could increase the capacity for further narrowing. The fibrotic changes in the airways of asthmatic subjects could prevent the transmission of distending forces and lead to long-term adaptation of the ASM to short lengths.


   Footnotes
 
Abbreviation: ASM = airway smooth muscle


   References
TOP
 Introduction
 Structural Alterations
 Functional Consequences
 Summary
 References
 

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